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Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)

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ClinicalTrials.gov Identifier: NCT01668784
Recruitment Status : Active, not recruiting
First Posted : August 20, 2012
Results First Posted : April 29, 2016
Last Update Posted : December 18, 2018
Sponsor:
Collaborator:
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Bristol-Myers Squibb

Tracking Information
First Submitted Date  ICMJE August 16, 2012
First Posted Date  ICMJE August 20, 2012
Results First Submitted Date March 28, 2016
Results First Posted Date April 29, 2016
Last Update Posted Date December 18, 2018
Actual Study Start Date  ICMJE September 27, 2012
Actual Primary Completion Date May 6, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2016)
Overall Survival (OS) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 months) ]
Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred after 398 deaths (70% of the total OS events needed for final analysis). At that time the data monitoring committee noted that the pre-specified boundary for OS (nominal significance level p < 0.0148) was crossed while no new safety signals that would affect continuation of the study were found. The study was stopped early by the Sponsor, Bristol-Myers Squibb (BMS) and the interim analysis became the final analysis. As a result, participants in the everolimus groups could be assessed for a crossover to nivolumab treatment if they met all inclusion criteria.
Original Primary Outcome Measures  ICMJE
 (submitted: August 16, 2012)
  • Overall survival [ Time Frame: Every clinic visit (every 2-4 weeks) up to 42 months ]
  • Overall survival [ Time Frame: Every 3 months up to 5 years ]
Change History Complete list of historical versions of study NCT01668784 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2016)
  • Investigator-assessed Objective Response Rate (ORR) at Primary Endpoint [ Time Frame: At 8 weeks post randomization, every 8 weeks for 12 months, and every 12 weeks until date of disease progression or death, up to May 2015 (approximately 30 months) ]
    ORR=number of participants with a best response of complete response (CR) or partial response (PR) divided by number of randomized participants. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Tumor assessments began at 8 weeks following randomization and continued every 8 weeks for the first year, then every 12 weeks thereafter until disease progression or death. CIs used Clopper and Pearson.
  • Investigator-assessed Duration of Objective Response at Primary Endpoint [ Time Frame: From date of first response to date of disease progression or death or censoring if no progression or death occurred, up to May 2015 (approximately 30 months) ]
    Duration of objective response is defined as the time from first response (complete response, CR or partial response, PR) to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. For participants who neither progress nor die, the duration of objective response were censored at the same time they were censored for the primary definition. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference. Based on Kaplan-Meier Estimates.
  • Investigator-assessed Time to Objective Response at Primary Endpoint [ Time Frame: Randomization to date of first response, up to May 2015 (approximately 30 months) ]
    Time to objective response is defined as the time from randomization to first response (complete response, CR or partial response, PR). CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.; PR=At least a 30% decrease in the sum of diameters of target lesions, the baseline sum diameters used as reference.
  • Investigator-assessed Time of Progression-free Survival (PFS) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 months) ]
    PFS=time from randomization to date of first documented tumor progression as determined by investigator (per RECIST 1.1 criteria or clinical) or death due to any cause, whichever occurred first. Participants who die without a reported prior progression and without subsequent anti-cancer therapy were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the date they were randomized. Participants who received any subsequent anti-cancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to or on initiation date of the subsequent anti-cancer therapy. Progressive disease: >=20% increase in sum of target lesion diameters and sum must show absolute increase of >=5mm; smallest sum on study as reference. Based on Kaplan-Meier Estimates.
  • Overall Survival (OS) by Programmed Death-Ligand 1 (PD-L1) Expression Level at Primary Endpoint [ Time Frame: Randomization to date of death or date of last contact for patients without documentation of death, up to May 2015 (approximately 30 months) ]
    Quantifiable PD-L1 expression=percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay. If the PD-L1 staining could not be quantified it was classified as: indeterminate=tumor cell membrane staining hampered for reasons attributed to biology of tumor biopsy specimen and not due to improper sample preparation or handling; not evaluable=tumor biopsy specimen was not optimally collected or prepared. Not evaluable determined from H&E process before the tumor biopsy specimen was sent for evaluation or from H&E process during PD-L1 evaluation; baseline PD-L1 expression=if more than one tumor biopsy specimen was available, the most recently collected specimen with a quantifiable result. If all specimens for a given participant are either indeterminate or not evaluable, then the PD-L1 expression was considered indeterminate as long as at least one specimen is indeterminate. Otherwise, PD-L1 expression was considered not evaluable.
  • Number of Participants With Serious Adverse Events, Death, Discontinuation Due to Adverse Events at Primary Endpoint [ Time Frame: Day of first dose to 30 days post final dose, up to May 2015 (approximately 30 months) ]
    Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.
  • Percentage of Participants With Disease-related Symptom Progression (DRSP) at Primary Endpoint [ Time Frame: Randomization until 398 deaths, up to May 2015 (approximately 30 months) ]
    Disease-related symptom progression rate (DRSPR)=a decrease of two points in the Functional Assessment of Cancer Therapy-Kidney Symptom Index - Disease Related Symptoms (FKSI-DRS) questionnaire relative to the participant's baseline FKSI-DRS score with no later increase above this threshold observed during the course of the study. The 9 items of the FKSI-DRS were summarized into a symptom scale ranging in score from 0 to 36, with 0 being the worst possible score and 36 being the best possible score. A single measure reporting a decrease of at least 2 units was considered disease-related symptom progression only if it was the last one available for the participant. In order to consider a questionnaire received as valid, over 50% of the items were to be completed. Calculated by the Clopper-Pearson method for each treatment group.
  • Number of Participants Meeting Marked Laboratory Abnormality Criteria in Specific Liver and Thyroid Tests at Primary Endpoint [ Time Frame: Day 1 to 30 days post last dose, up to May 2015 (approximately 30 months) ]
    Aspartate aminotransferase, AST. Alanine aminotransaminase, ALT. Total bilirubin, tBIL. Thyroid stimulating hormone, TSH. Upper limit of normal (ULN). Units per Liter (U/L). Results reported in International System of Units (SI).
  • Number of Participants With Abnormal Hematology and Serum Chemistry Laboratory Parameters by Worse CTC Grade - SI Units [ Time Frame: Day 1 to 30 days post last dose, up to May 2015 (approximately 30 months) ]
    Common Terminology Criteria (CTC) version 4.0 in International System of Units (SI); Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Hematology parameters=Hemoglobin (Gr 3: < 8.0 g/dL), Platelet Count (Gr 3: 25.0 -< 50.0*10^9 c/L; Gr 4: < 25.0*10^9 c/L), Leukocyte Count (Gr 3: 1.0 -< 2.0*10^3 c/µL; Gr4: < 1.0*10^3 c/µL), Absolute Lymphocyte Count (Gr 3: 0.2 -< 0.5*10^3 c/µL; Gr 4: < 0.2*10^3 c/µL), Absolute Neutrophil Count (Gr 3: 0.5 - < 1.0*10^3 c/µL; Gr 4: < 0.5*10^3 c/µL). Liver Function parameters=Alkaline Phosphatase (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), AST (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), ALT (Gr 3: > 5.0 - 20.0 U/L * ULN; Gr 4: > 20.0 U/L * ULN), tBIL (Gr 3: > 3.0 - 10.0 mg/dL * ULN; Gr 4: > 10.0 mg/dL * ULN). Renal parameter=Creatinine (Grade: Gr3: > 3.0 - 6.0 mg/dL *ULN; Gr4: > 6.0 mg/dL *ULN). Cells per microliter (c/µL). Cells per Liter (c/L). Grams per deciliter (g/dL). Milligrams per deciliter (mg/dL).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 16, 2012)
  • Progression-free survival [ Time Frame: Disease assessments every 8 weeks after randomization for every 12 months then 12 weeks until progression of disease ]
  • Objective response rate [ Time Frame: Disease assessments every 8 weeks after randomization for every 12 months then 12 weeks until progression of disease ]
  • Duration of objective response [ Time Frame: Disease assessments every 8 weeks after randomization for every 12 months then 12 weeks until progression of disease ]
  • Duration of overall survival (OS) in Programmed death-ligand 1 (PD-L1) positive vs negative subgroups [ Time Frame: At every clinic visit (every 2-4 weeks) while on treatment and then every 3 months ]
  • Safety will be analyzed through the incidence of adverse events, serious adverse events [ Time Frame: Continuously throughout study treatment and up to 100 days from last dose ]
  • Safety will be analyzed through the incidence of laboratory abnormalities [ Time Frame: Continuously throughout study treatment and up to 100 days from last dose ]
  • Disease related symptom progression rate [ Time Frame: Baseline, Day 1 of each cycle (starting with cycle 2), then at first 2 follow-up visits ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Nivolumab (BMS-936558) vs. Everolimus in Pre-Treated Advanced or Metastatic Clear-cell Renal Cell Carcinoma (CheckMate 025)
Official Title  ICMJE A Randomized, Open-Label, Phase 3 Study of Nivolumab (BMS-936558) vs. Everolimus in Subjects With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy
Brief Summary The purpose of the study is to compare the clinical benefit, as measured by duration of overall survival, of Nivolumab vs. Everolimus in subjects with advanced or metastatic clear-cell renal cell carcinoma who have received prior anti-angiogenic therapy
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced or Metastatic (Medically or Surgically Unresectable) Clear-cell Renal Cell Carcinoma
Intervention  ICMJE
  • Biological: Nivolumab
    Other Name: BMS-936558
  • Drug: Everolimus
    Other Name: Afinitor
Study Arms
  • Experimental: Arm 1: Nivolumab
    Nivolumab 3 mg/kg solution intravenously every 2 weeks until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
    Intervention: Biological: Nivolumab
  • Active Comparator: Arm 2: Everolimus
    Everolimus 10 mg tablets by mouth daily until documented disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends
    Intervention: Drug: Everolimus
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 15, 2017)
1068
Original Estimated Enrollment  ICMJE
 (submitted: August 16, 2012)
822
Estimated Study Completion Date August 14, 2019
Actual Primary Completion Date May 6, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

  • Men & women ≥18 years of age
  • Histologic confirmation of renal cell carcinoma (RCC) with clear-cell component
  • Advanced/metastatic RCC
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • Received 1 or 2 prior anti-angiogenic therapy regimens in advanced or metastatic setting
  • No more than 3 total prior systemic treatment regimens in the advanced or metastatic setting, and evidence of progression on or after last treatment regimen received and within 6 months of enrollment
  • Karnofsky Performance Score ≥70%

Exclusion Criteria:

  • Any Central Nervous System (CNS) metastases or history of CNS metastases
  • Prior therapy with an Mammalian target of rapamycin (mTOR) inhibitor
  • Any active known or suspected autoimmune disease
  • Uncontrolled adrenal insufficiency
  • Active chronic liver disease
  • Prior malignancy active within past 3 years, except for locally curable cancers
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Ireland,   Israel,   Italy,   Japan,   Norway,   Poland,   Romania,   Russian Federation,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Hungary
 
Administrative Information
NCT Number  ICMJE NCT01668784
Other Study ID Numbers  ICMJE CA209-025
2011‐005132‐26 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Bristol-Myers Squibb
Study Sponsor  ICMJE Bristol-Myers Squibb
Collaborators  ICMJE Ono Pharmaceutical Co. Ltd
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Bristol-Myers Squibb
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP